Down syndrome (DS) acute lymphoblastic leukemia (ALL), more frequent in pediatric age than in adulthood, still have a worse outcome compared with non-DS population, mainly due to their intrinsic susceptibility to chemotherapeutic drugs toxicity. Furthermore, in the last years, it has been shown that the overexpression of CRLF2 and a Ph-like signature are relatively more frequent in DS patients. We report a case of a DS patient who developed a Ph-like ALL, 21 years after a first diagnosis of B-ALL, successfully treated with blinatumomab after failure of conventional chemotherapy.